This application is a national stage filing of PCT International Application No. PCT/FI98/00977, filed Dec. 11, 1998, the content of which is incorporated herein by reference.
The present invention relates to transmucosal delivery of levosimendan or a pharmaceutically acceptable salt thereof, particularly delivery via oral and nasal mucosa. The invention also relates to transmucosal, particularly intraoral and intranasal, e.g. buccal, sublingual or sinuidal, preparations comprising levosimendan or a pharmaceutically acceptable salt thereof as the active ingredient.
Levosimendan, which is the (-)-enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile (I), and the method for its preparation is described e.g. in EP 565546 B1. Levosimendan is potent in the treatment of heart failure and has significant calcium dependent binding to troponin. The use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921. Pharmacokinetics of levosimendan in man after i.v. and oral dosing is described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol., 26(Suppl. 1), S57-S62, 1995. 
Clinical studies have confirmed the beneficial effects of levosimendan in heart failure patients.
It has now been found that therapeutically effective and steady serum levels of levosimendan are rapidly achieved by administering levosimendan transmucosally, preferably to oral or nasal mucosa. Furthermore, it has been found that by administering levosimendan transmucosally the occurence of undesired side effects such as headache and palpitation connected to the oral administration of levosimendan can be reduced or totally avoided. It is now believed that active metabolites formed in the gastrointestinal tract by intestinal bacteria contribute to the observed undesired effects. The formation of metabolites in the gastrointestinal tract can be reduced or totally avoided by transmucosal administration.
Accordingly, the object of the invention is to provide a method for administering transmucosally, i.e. to and across a mucosal surface, levosimendan or a pharmaceutically acceptable salt thereof. The mucosal surface is preferably oral or nasal mucosa such as the buccal mucosa, the sublingual mucosa, the sinuidal mucosa, the gum, or the inner lip.
The present invention also provides transmucosal, particularly intraoral and intranasal, e.g. buccal, sublingual or sinuidal, preparations comprising levosimendan or a pharmaceutically acceptable salt thereof as a therapeutically active ingredient.
The present invention also provides the use of levosimendan or a pharmaceutically acceptable salt there6f in the manufacture of a medicament for transmucosal administration, particularly to oral and nasal mucosa, of levosimendan or a pharmaceutically acceptable salt thereof.
Furthermore the present invention provides a method for treating heart failure comprising administering transmucosally, particularly to oral and nasal mucosa, a therapeutically effective amount of levosimendan or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.
Furthermore the present invention provides a method of administering transmucosally, particularly to oral and nasal mucosa, levosimendan or a pharmaceutically acceptable salt thereof to a patient, wherein the method comprises contacting an intact mucous membrane with a source of levosimendan or a pharmaceutically acceptable salt thereof, and maintaining said source in contact with said mucous membrane for a sufficient time period to deliver said levosimendan or a pharmaceutically acceptable salt thereof to the patient.